Effects of THC on reversal learning and extradimensional shifts in rhesus monkeys
Michael A. Taffe
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA
CD (and CR) stimuli
learning in chimpanzee, oragutan, macaque and squirrel monkeys
10
0
IDS (and IDR) stimuli
SD
SR
CD
CR
IDS
IDR
EDS
20
CD
CR
IDS
0.2 THC
0.3 THC
**
5
0
CD
CR
CD
CR
Reversal Learning (90 min)
4
2
0
SR
0.1 THC
10
EDR
10
8
6
SD
Veh
N=8
15
Experienced Monkeys (N=11), One Session, 6/6 criterion
EDS (and EDR) stimuli
sqrt(ETC)
THC impairs:
15
5
SUPPORT: U.S.P.H.S. grants: DA018418 and DA024194.
Introduction
20
25
Extradimensional Shift
Reversal Learning (20 min)
IDR EDS EDR
30
25
20
Veh
0.1 THC
0.2 THC
0.3 THC
N=7
5
0
CR
*
CD
IDS
EDS
CD
Veh + Veh
0.1 SR + Veh
0.3 THC + 0.1 SR
0.3 THC + Veh
N=5
Task administered in homecage
during telemetry experiment
No other tasks administered
4 runs of task at indicated times
relative to THC administration
Baseline
60 min
90 min
120 min
Task administered at the end of behavioral session
45 min Session Pre-treat
CR
26
24
22
20
18
16
14
12
10
*
Base Veh
*
N=8
0.1 0.2 0.3
THC (mg/kg)
80
70
60
50
40
30
20
10
0
20 min Session Pre-treat
*
*
N=9
Base Veh 0.1 0.2 0.3
THC (mg/kg)
N = 10
Veh
0.1 0.2 0.3
SR (mg/kg)
THC slows bimanual motor performance in a dose
dependent manner for several hours post-injection.
THC does not alter Extra-dimensional Shift errors.
(Criterion: 12/15 correct)
(Branch et al. 1980; Pieper 1976; Schulze et al. 1988; Schulze et al. 1989)
100
90
80
70
60
50
40
30
20
10
0
EDR
A longer pre-treatment interval which places the
behavioral session in the hypothermia phase of
the temperature response does not result in
increased reversal errors.
10
CD
N=7
Veh
0.1 THC
0.2 THC
0.3 THC
0.2-0.3 mg/kg THC i.m. increases reversal errors.
15
Increased errors are observed when contingencies are reversed and when
the pertinent stimulus dimension shifts. Error patterns are similar whether
run in a multi-session or single session test protocol.
80
70
60
50
40
30
20
10
0
Seconds
25
30
Bimanual Motor Skill
Seconds
CONCLUSIONS: The study demonstrated that reversal learning and extradimensional shift
executive cognitive tasks are only minimally affected by doses of THC which substantially
affect motor performance and thermoregulation. Combined with prior observations this
suggests a relative insensitivity of frontal cortex mediated tasks over temporal cortex
mediated tasks to acute THC.
Errors to Criterion
RESULTS: Acute administration of THC only minimally impaired performance on reversal
learning and extradimensional shifts up to doses which substantially suppressed responding.
A test of bimanual motor performance was impaired, and body temperature reduced, in a
dose dependent fashion. This hypothermia was reversed by co-administration of the CB1
antagonist rimonabant.
30
SD (and SR) stimuli
Errors to Criterion
METHODS: Rhesus monkeys challenged with THC (0.1-0.3 mg/kg, i.m.) 20 and 90 minutes
prior to the test sessions during which they were evaluated on reversal learning and
extradimensional shift measures adapted from the CANTAB (CAmbridge
Neuropsychological Test Automated Battery) Intradimensional/Extradimensional Attentional
Set Shifting task.
Naive Monkeys (N=8), Multisession, 18/20 criterion
sqrt(ETC)
AIMS: Cannabis remains the most commonly used illicit recreational psychoactive
drug. Recent advances in understanding of the distribution and function of components of
the brain endocannabinoid systems motivate a further specification of the behavioral
consequences of acute exposure to the primary psychoactive ingredient of cannabis, 9tetrahydrocannabinol (THC). This study was designed to determine relative effects of acute
THC on two cognitive executive functions that have been associated with intact prefrontal
cortical function.
THC Impairs Reversal, not ED Shift
Reversal Learning and
Extradimensional Shifts with CANTAB
Errors to Criterion
Abstract
recognition memory in chimpanzee and macaque
(Aigner 1988; Ferraro and Grilly 1974; Schulze et al. 1988; Schulze et al. 1989)
spatial delayed response in macaques (Rupniak, 1991)
time estimation in macaques, chimpanzee and orangutan
THC induces hypothermia in monkeys
Δ9-tetrahydrocannabinol
Rimonabant (SR141716)
(0.1-0.3 mg/kg i.m.; 1:1:18 Emulphor:EtOH:Saline Veh)
(data previously presented: CPDD Annual Meeting 2001)
0.50
0.25
0.00
-0.25
-0.50
-0.75
-1.00
-1.25
-1.50
Vehicle
0.3 mg/kg THC
0.1 mg/kg SR
0.1 SR + 0.3 THC
-1.75
Minutes Post-Injection
300
270
240
210
180
150
120
90
60
30
0
-30
THC-induced cognitive impairment is observed as
early as 30 min after i.m. injection.
Change from Baseline ( C)
0.75
N=6
0.50
THC-induced motor impairment is stable from 60 to
120 min after i.m. injection.
0.25
0.00
-0.25
-0.50
Vehicle
0.3 mg/kg THC
0.3 mg/kg SR
SR + THC
-0.75
-1.00
* SR and SR+THC differ from THC alone
-1.25
Minutes Post-Injection
Rimonabant blocks THC-induced hypothermia at a dose which
does not affect temperature when administered alone.
300
0.2-0.3 mg/kg THC, i.m., interferes
with spatial working memory although
effects were not dependent on task
difficulty.
N=4
0.75
270
0.1
0.2
0.3
THC (mg/kg)
1.00
240
Veh
Minutes Post-Injection
210
Base
-1.25
180
20%
-1.00
-60
40%
Vehicle
0.1 mg/kg THC
0.2 mg/kg THC
0.3 mg/kg THC
-0.75
-90
*
Open symbols indicate significant difference (p<0.05) from baseline
and vehicle; shaded symbols indicate significant difference from baseline only.
-0.50
150
0.2-0.3 mg/kg THC, i.m., interferes
with visual-spatial associative learning
in a difficulty dependent manner.
9 10 11 12 13 14 15 16 17 18 19 20
120
Repeat Attempts
(learning)
8
90
Initial Attempt
(memory)
0.1 0.2 0.3
THC (mg/kg)
7
60
0.1 0.2 0.3
THC (mg/kg)
6
Hours Post-Injection
60%
0%
5
-0.25
30
0%
N=4
4
Δ9-tetrahydrocannabinol (THC) impairs reversal
learning but not extradimensional shift performance
Hypothermic responses to THC are observed
starting about 1.5-2 hrs after i.m. injection in the
monkey and are reversed by Rimonabant.
0.00
0
*
3
0.25
-30
20%
*
2
Summary
N = 10
0.50
-60
*
1 Stimulus
2 Stimuli
3 Stimuli
4 Stimuli
*
-1 1
0.75
-90
*
Veh
40%
35.5
Body Temperature
60%
80%
N = 10
Body Temperature
*
Percent Correct Trials
*
N=4
THC significantly reduces body
temperature with maximum effect
observed 3-6 hrs after intramuscular
administration.
36.0
-90
-60
-30
0
30
60
90
120
150
180
210
240
270
300
330
360
390
420
450
Data Sciences International (Transoma)
80%
100%
36.5
Change from Baseline ( C)
Radiotelemetric monitoring of subcutaneous
temperature and spontaneous locomotor activity.
Self-Ordered Spatial Search Task
*
Base
(Lafayette Instruments / Campden)
100%
Veh
CAmbridge Neuropsychological Test Automated Battery
vsPAL Task
Base
Male rhesus macaques
Percent Correct Trials
Methods
Choice
Vehicle
0.1 mg/kg THC
0.2 mg/kg THC
0.3 mg/kg THC
37.0
Body Temperature
Sample
The present goal was to use tasks shown to depend on intact
frontal cortical function to further determine the
breadth or selectivity of acute THC effects on complex
cognition in monkeys.
37.5
Change from Baseline ( C)
THC impairs Spatial Memory
The distribution of the CB1 receptor in macaque brain is highly
similar to that of human brain (Eggan and Lewis 2006). High
levels of expression were noted in frontal and temporal
lobe regions.
Body Temperature ( C)
(Pieper 1976; Schulze et al. 1988; Schulze et al. 1989; Snyder et al. 1975)
The magnitude of the THC effect on the reversal and
ED Shift tasks relative to prior observations with
SOSS and vsPAL tasks is unlikely to be related to
pre-treatment interval.